Project Summary/Abstract This proposal describes a 5-year research and career development plan that will allow Dr. Roberto Ricardo Gonzalez to achieve his long-term goal of becoming an independently funded physician-scientist studying how tissue-resident innate immune cells coordinate with the tissue niche during development, homeostasis, and disease. Dr. Ricardo Gonzalez is an assistant professor of dermatology at the University of California, San Francisco. The candidate has a long-standing interest in studying how type 2 immune responses are altered in disease. He recently published a study describing a tissue-organizing transcriptome defining type 2 innate lymphoid cells (ILC2s) from distinct organs, that emphasized these cells as critical sources of type 2 cytokines in the skin and other tissues independent of the microbiota. Additional preliminary data suggest ILC2s are laid out in the skin early in development, and that their function is coupled to epithelial function. The long-term goal of the proposed study is to understand the fundamental role of type 2 immune responses in maintaining epithelial health and will test the hypothesis that type 2 immunity is critical in the maintenance of optimal skin tissue function and homeostasis. To investigate this, he proposes the following three complementary approaches to evaluate how type 2 immunity influences skin homeostasis. Aim 1 will elucidate how ILC2s and type 2 immunity are critical for maintaining proper function of the skin and epithelial stem cell fitness. Aim 2 will dissect how the type 2 immune tone is set in tissues during development and how this influences tissue homeostasis and inflammation. Aim 3, will develop new tools that will allow for spatiotemporal control of trafficking and genome editing of ILC2s and other lymphocyte populations. In this study, the candidate will use a combination of mechanistic studies and cutting-edge technologies that will provide him with additional training and expertise to become an independent investigator. Under the mentorship of Dr. Richard Locksley, an expert in allergic immunity, and in collaboration with his multidisciplinary scientific advisory committee, the candidate, mentor and scientific advisors have developed a career development plan for Dr. Ricardo Gonzalez to gain additional experience in state of the art immunology and imaging research techniques, biostatistics, epithelial and stem cell biology, and scientific communication. Overall, the experiments proposed would expand our fundamental understanding of how type 2 immunity influences skin homeostasis and specifically will shed light into the non-immune novel roles of this immune axis.